Continuously non-malleable codes with split-state refresh

Non-malleable codes for the split-state model allow to encode a message into two parts, such that arbitrary independent tampering on each part, and subsequent decoding of the corresponding modified codeword, yields either the same as the original message, or a completely unrelated value. Continuously non-malleable codes further allow to tolerate an unbounded (polynomial) number of tampering attempts, until a decoding error happens. The drawback is that, after an error happens, the system must self-destruct and stop working, otherwise generic attacks become possible. In this paper we propose a solution to this limitation, by leveraging a split-state refreshing procedure. Namely, whenever a decoding error happens, the two parts of an encoding can be locally refreshed (i.e., without any interaction), which allows to avoid the self-destruct mechanism in some applications. Additionally, the refreshing procedure can be exploited in order to obtain security against continual leakage attacks. We give an abstract framework for building refreshable continuously non-malleable codes in the common reference string model, and provide a concrete instantiation based on the external Diffie–Hellman assumption. Finally, we explore applications in which our notion turns out to be essential. The first application is a signature scheme tolerating an arbitrary polynomial number of split-state tampering attempts, without requiring a self-destruct capability, and in a model where refreshing of the memory happens only after an invalid output is produced. This circumvents an impossibility result from a recent work by Fujisaki and Xagawa (Asiacrypt 2016). The second application is a compiler for tamper-resilient read-only RAM programs. In comparison to other tamper-resilient RAM compilers, ours has several advantages, among which the fact that, in some cases, it does not rely on the self-destruct feature

The relative timing of trunk muscle activation is retained in response to unanticipated postural-perturbations during acute low back pain

The purpose of this study was to assess the activation of the erector spinae (ES) and external oblique (EO) in response to unanticipated, bi-directional postural perturbations before and after the induction of acute low back pain (LBP) in healthy individuals. An experimental session consisted of a baseline, control, and an acute LBP condition. For the control and acute LBP condition, isotonic or hypertonic saline (HS), respectively, was injected into the right ES muscle. In each condition, participants stood on a moveable platform during which 32 randomized postural perturbations (8 repetitions of 4 perturbation types: 8 cm anterior slides, 8 cm posterior slides, 10° anterior tilts, and 10° posterior tilts) with varying inter-perturbation time intervals were performed over a period of 4–5 min. Bilateral surface electromyography (EMG) was recorded from the ES and EO in addition to subjective pain records. During the acute LBP condition: (1) the onset time of the ES and EO was delayed for the forward and backward sliding perturbations (P < 0.05); (2) EMG amplitude was reduced bilaterally for all perturbations (P < 0.05); (3) the order of activation and interval between the onset times of the ES and EO were unaltered and (4) ES, but not EO, activity was adjusted to account for the directional differences between the perturbations. This study revealed that re-establishment of posture and balance was a result of the individuals’ ability to rapidly modulate ES with respect to EO activity and that the bi-directional postural responses, although shifted in time and amplitude, retained temporal features in the presence of acute LBP

Heart-Kidney Interaction: Epidemiology of Cardiorenal Syndromes

Cardiac and kidney diseases are common, increasingly encountered, and often coexist. Recently, the Acute Dialysis Quality Initiative (ADQI) Working Group convened a consensus conference to develop a classification scheme for the CRS and for five discrete subtypes. These CRS subtypes likely share pathophysiologic mechanisms, however, also have distinguishing clinical features, in terms of precipitating events, risk identification, natural history, and outcomes. Knowledge of the epidemiology of heart-kidney interaction stratified by the proposed CRS subtypes is increasingly important for understanding the overall burden of disease for each CRS subtype, along with associated morbidity, mortality, and health resource utilization. Likewise, an understanding of the epidemiology of CRS is necessary for characterizing whether there exists important knowledge gaps and to aid in the design of clinical studies. This paper will provide a summary of the epidemiology of the cardiorenal syndrome and its subtypes

Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

Idiosyncratic adverse drug reactions are unpredictable, dose independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkage between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells that required HLA-B*57:01 molecules for their function. However, the mechanism by which abacavir induces this pathologic T cell response remains unclear. Here we show that abacavir can bind within the F-pocket of the peptide-binding groove of HLA-B*57:01 thereby altering its specificity. This supports a novel explanation for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can alter the repertoire of self-peptides presented to T cells thus causing the equivalent of an alloreactive T cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir, and that were recognized by T cells of hypersensitive patients. The assays we have established can be applied to test additional compounds with suspected HLA linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA linked hypersensitivities as well as guide the development of safer drugs

Class II phosphoinositide 3-kinase C2 beta regulates a novel signaling pathway involved in breast cancer progression

It is now well established that the enzymes phosphoinositide 3-kinases (PI3Ks) have a key role in the development and progression of many cancer types and indeed PI3Ks inhibitors are currently being tested in clinical trials. Although eight distinct PI3K isoforms exist, grouped into three classes, most of the evidence currently available are focused on one specific isoform with very little known about the potential role of the other members of this family in cancer. Here we demonstrate that the class II enzyme PI3K-C2β is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2β regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2β expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2β in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. Investigation of the mechanism of the PI3K-C2β-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2β regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2β inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2β is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2β plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2β may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification

Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified

The Healthy Men Study: An Evaluation of Exposure to Disinfection By-Products in Tap Water and Sperm Quality

BackgroundChlorination of drinking water generates disinfection by-products (DBPs), which have been shown to disrupt spermatogenesis in rodents at high doses, suggesting that DBPs could pose a reproductive risk to men. In this study we assessed DBP exposure and testicular toxicity, as evidenced by altered semen quality.MethodsWe conducted a cohort study to evaluate semen quality in men with well-characterized exposures to DBPs. Participants were 228 presumed fertile men with different DBP profiles. They completed a telephone interview about demographics, health history, water consumption, and other exposures and provided a semen sample. Semen outcomes included sperm concentration and morphology, as well as DNA integrity and chromatin maturity. Exposures to DBPs were evaluated by incorporating data on water consumption and bathing and showering with concentrations measured in tap water. We used multivariable linear regression to assess the relationship between exposure to DBPs and adverse sperm outcomes.ResultsThe mean (median) sperm concentration and sperm count were 114.2 (90.5) million/mL and 362 (265) million, respectively. The mean (median) of the four trihalomethane species (THM4) exposure was 45.7 (65.3) μg/L, and the mean (median) of the nine haloacetic acid species (HAA9) exposure was 30.7 (44.2) μg/L. These sperm parameters were not associated with exposure to these classes of DBPs. For other sperm outcomes, we found no consistent pattern of increased abnormal semen quality with elevated exposure to trihalomethanes (THMs) or haloacetic acids (HAAs). The use of alternate methods for assessing exposure to DBPs and site-specific analyses did not change these results.ConclusionsThe results of this study do not support an association between exposure to levels of DBPs near or below regulatory limits and adverse sperm outcomes in humans

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

CD8[superscript +] T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8[superscript +] T cell response, with limited bystander activation of non-HIV memory CD8[superscript +] T cells. HIV-specific CD8[superscript +] T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8[superscript +] T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8[superscript +] T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.Bill & Melinda Gates FoundationCollaboration for AIDS Vaccine DiscoveryWitten Family FoundationDan and Marjorie SullivanUrsula BrunnerGary and Loren CohenMark and Lisa Schwartz Foundation,International AIDS Vaccine Initiative (UKZNRSA1001)National Institute of Allergy and Infectious Diseases (U.S.) (R37AI067073)Center for AIDS Research (P30 AI060354